Transdermal drug delivery is generally considered to be delivery of a therapeutic agent through the skin of a patient, for distribution of the therapeutic agent within the body by the circulation of the blood. After passing through the outer layers of skin, the therapeutic agent diffuses into the capillaries or tiny blood vessels in the skin, from which it is transported to the circulating blood. Additionally, after having diffused into the skin, the drug may enter into the lymphatic system, and thence be carried to the circulating blood. Topical drug delivery Is generally considered to be delivery to a topical wound, lesion, area affected by a skin disorder etc., of a medicament for the purposes of combatting infections, accelerating wound healing, relieving pain, managing skin disorders etc., by treatment of the localized area.
It may be advantageous to administer some therapeutic agents, such as non-steroidal anti-inflammatory drugs (NSAID), to tissues well below the skin, such as muscles or joints, by topical application to the skin above the area requiring treatment. This is often referred to as either topical or transdermal drug delivery.
A feature which most transdermal drug delivery devices have in common is the provision of a skin compatible adhesive for attaching the device to the skin. For such a device to work effectively, there should be intimate and continuous contact between the patient's skin and the skin contacting layers of the device, to ensure control over the rate of drug delivery. However, the skin contacting adhesive should not deleteriously interfere with the drug's properties, nor with its migration to the skin surface. This means that the choice of adhesive is dictated to a large extent by the choice of drug to be delivered, rather than by allowing a free selection of skin compatible adhesives on the basis of their own inherent properties.
A significant number of pharmaceutical substances are macromolecular in nature, having molecular weights of about 10 kilodaltons or higher, e.g. polypeptides, glycoproteins, etc. Examples of polypeptide and glycoprotein drugs are erythropoietin (30,000 daltons), parathyroid hormone (9,500 daltons), human growth hormone (22,000 daltons), follicle-stimulating hormone (36,000 daltons), interleukin-2 (15,000 daltons), and interferon-alpha (20,000 daltons). Polypeptide and glycoprotein drugs are generally degraded in the stomach and are poorly absorbed in the gastrointestinal tract, so that conventional oral administration is not a viable method of delivery. The normal method of delivery is injection of solutions.
Many polypeptide drugs have very short half-lives once they reach the bloodstream. For example, human growth hormone has a half-life of less than 25 minutes, and parathyroid hormone has a half-life of less than 15 minutes (see R. A. Siegel and Robert Langer, Pharmaceutical Research, 1 2 (1984)). Drugs with very short half-lives are generally particularly well suited for a sustained release delivery system such as transdermal delivery, provided that sustained release is not contraindicated by the mode of action of the drug.
Despite the desirability of transdermal delivery of macromolecular polypeptides, there are difficulties which have prevented its commercial realization. The diffusion of macromolecular drugs through conventional skin adhesives is normally too slow to be therapeutically beneficial. The diffusion rate can be increased by causing the adhesive to become grossly swollen with a solvent for the drug, but this will impair its adhesion properties. In addition, drugs of molecular weight over about 500 daltons pass through the skin with great difficulty. Passage of individual macromolecular drugs through the skin is normally prohibitive because of their large size. Even smaller polypeptide drugs, such as luteinizing hormone-releasing factor LHRH (1,200 daltons), LHRH agonists such as nafarelin (1,300 daltons), vasopressin (1,100 daltons), desmopressin (1,100 daltons), ornipressin (1,100 daltons), and octreotide (1000 daltons), can not be expected to penetrate the layers of skin in order to enter the circulating blood in therapeutically useful quantities. The outermost layer of skin, called the stratum corneum and consisting of dead, keratinized epidermal cells, is the main barrier to the entry of drugs into the body by transdermal delivery.
At least partial removal of the stratum corneum at the area to which such macromolecular drugs are to be delivered may well be necessary.
There is also a need in the marketplace for devices which collect substances from a mammalian body, over an extended period of time, for subsequent analysis. Such devices could usefully be provided in the form of adhesive patches for application to a subject's skin and later removal, and containing a form of collection reservoir into which substances from the body migrate. These are useful in monitoring glucose levels, etc., and in detecting illegal substance use.